Tenofovir, also known as 9-[2-(R)-(phosphonomethoxy)propyl]adenine (PMPA), is represented by the following structure of Formula I:

Tenofovir is approved for commercial use as in the form of Tenofovir disoproxil fumaric acid salt, chemically known as 9-[(R)-2-[[bis[[(isopropoxycarbonyl) oxy]methoxy]phosphinyl]methoxy]propyl]adenine fumarate, is represented by the following structure of Formula:

Tenofovir disoproxil fumarate is a highly potent antiviral agent and is available in the market under the brand name VIREAD® in the form of 300 mg of oral tablets and in combination with other antiviral agents.
Patent publication WO 94/03467 (“the '467 publication”) and U.S. Pat. No. 5,733,788 (“the '788 patent”) discloses a process for preparation of tenofovir by reaction of 9-[2-(R)-hydroxypropyl) adenine with di-(2-alkyl)-p-toluenesulfonyloxy methyl phosphonate in presence of strong bases such as sodium hydride, lithium hydridein dimethyl formamide followed by dealkylation with bromotrimethyl silane in Acetonitrile. The process disclosed in the '788 patent is schematically represented as follows:

U.S. Pat. No. 5,922,695 (“the '695 patent”) discloses a process for preparation of tenofovir by reaction of 9-[2-(R)-hydroxy propyl)adenine with diethyl-p-toluenesulfonyloxy methyl phosphonate in presence of Lithium tert-butoxide in Tetrahydrofuran followed by dealkylation with bromotrimethylsilane in Acetonitrile.
U.S. Pat. No. 6,465,649 (“the '649 patent”) discloses a process for preparation of tenofovir by dealkylation of 9-[2-(R)-(diethyl phosphonomethoxy)propyl]adenine with chlorotrimethylsilane in chlorobenzene.
The '649 patent further described conventional methods for dealkylating phosphonate esters include reaction with aqueous solutions of concentrated HCl or HBr are inappropriate as many of the functional groups on the phosphonates are acid labile, which cannot tolerate these harsh acidic conditions for instance amino group as in the case of tenofovir is readily converted into keto compound (Hypoxanthine impurity) under these concentrated acidic conditions.
The '649 patent also mentions that chlorotrimethylsilane is less reactive and can be used only for the deprotection of the more labile phosphonate esters for example dimethyl phosphonate esters. The deprotection of diethyl phosphonate ester requires long reaction times resulting in unsatisfactory yields. In order to overcome this problem, the use of an activating agent like sodium or lithium iodide to the reaction medium results in faster reaction times. However, the use of such salts leads to metal contamination of the final product and thus additional process steps such as solvent crystallization required to remove.
Moreover, the use of halo trimethylsilanes such as bromo and chlorotrimethylsilanes described in the aforementioned literature for dealkylation reaction are moisture sensitive, expensive and requires special handling procedures due to its highly corrosive in nature, particularly on commercial scale and thus require more care to use; which in turn result to an increase in the manufacturing cost.
U.S. Pat. No. 8,049,009 (“the '009 patent”) discloses a process for preparation of tenofovir by reaction of 9-[2-(R)-hydroxypropyl) adenine with diethyl-p-toluenesulfonyloxy methyl phosphonate in presence of Magnesium tert-butoxide in dimethyl formamide followed by dealkylation with an acid such as aqueous HBr, aqueous HCl, HBr in acetic acid and HCl gas in isopropyl alcohol.
The literature mentioned above for instance “the '009 patent further discloses” isolation of the intermediate compound phosphonate diester, prior to the dealkylation is performed by complete removal of the dimethyl formamide from the reaction medium. Removal of the high boiling solvent dimethyl formamide from the reaction mixture would require prolonged period of time at higher temperature, this leads to degradation of the low melting phosphonate diester product. Accordingly, extensive purification procedures are required in order to obtain the necessary quality of the end product and results low product yield thereby making the process quite expensive.
It would be desirable to provide a process for the preparation of tenofovir, which is simple and cost effective; and a process for its use thereof in the preparation of tenofovir disoproxil fumarate in a convenient, cost efficient manner and on a commercial scale.
The present invention provides a process for preparation of tenofovir using suitable dealkylating Ionic complexes that are away from the aforementioned difficulties such as moisture sensitive, corrosive and expensive dealkylating reagents and avoids additional process steps like solvent distillation to minimize the product degradation. The process of the present invention can be practiced on an industrial scale, and also can be carried out without sacrifice of overall yield.